The application is directed to novel maleiimido compounds and conjugates made therefrom.
Progress in immunochemistry has required the preparation of numerous protein-protein or protein-hapten conjugates for analytical and preparative techniques. For a review of protein modifications see Means, G. E. and Feeney, R. E., Bioconjugate Chem., (1990), 1, 2-12 and M. Brinkley, Bioconjugate Chem., (1992) 3, 2-13. The attachment of cytotoxic drugs to tumor-localizing monoclonal antibodies (immunotoxins) is an approach to chemotherapy which is rapidly gaining acceptance. See Koppel, G. A., Bioconjugate Chem., 1990, 1, 13-23. Many reagents for the preparation of such conjugates have been disclosed and studied extensively. See Kitagawa et al, Chem. Pharm. Bull., 29(4), 1130-1135 (1981) and references cited therein. The so-called crosslinking reagents which have been developed are typically designed to have specific reactivity with functional groups contained in each reactant. Both homoand heterobifunctional reagents are known with the latter being most desirable. Since heterobifunctional crosslinkers possess two selectively reactive groups which can be used to link proteins or other moieties in a stepwise and specific manner, the occurrence of unwanted side reactions such as the formation of homo-protein polymers is desirably avoided.
A common type of heterobifunctional crosslinker contains an amine reactive group (e.g., N-hydroxysuccinimide esters) and a sulfhydryl reactive group (e.g., maleiimide, haloacetyl functions and reactive disulfides) connected by a spacer group. However, there are instances where a hapten and/or a peptide does not contain one of the common functional groups such as an .epsilon.-amino-lysine residue and linking such materials to proteins becomes increasingly more difficult. Conventional crosslinkers are inadequate for this purpose. One approach is to chemically modify the material, but this technique is not satisfactory in all instances since this often changes the desired biological or chemical behavior of the compound. While the compound of interest may lack a linkable amino group it may contain a hydroxyl group. Known crosslinking materials may be used with such compounds but the resulting ester-linked derivatives typically suffer from the stability limitations inherent in the ester moiety. See, for example, Hermentin, P. et al. Bioconjugate Chem., 1990, 1, 100-107. Crosslinking chemistry which typically provides more stable hydroxyl linking such as in the formation of a urethane bond from an isocyanate and an alcohol group is always preferred. See, for example, Lynn, K. R. et al, J. Phys. Chem., 1972, 69, No. 2, pp. 687-689 and Adams, P. et al., Chem. Rev., 1965, 65, 567.
Accordingly as the state of the art advances there is a continuing demand for new materials to perform these functions.
It is therefore the object of this invention to provide novel heterobifunctional compounds.
It is another object to provide heterobifunctional compounds which can link a compound having an alcohol group or an amine group with a compound having a thiol group.
A further object is to provide heterobifunctional compounds which have a terminal isocyanate group and a terminal maleiimido group.